2.1 Vaccines
Vaccines have traditionally consisted of live attenuated pathogens, whole inactivated organisms or inactivated toxins. In many cases these approaches have been successful at inducing immune protection based on antibody mediated responses. However, certain pathogens, e.g., HIV, HCV, TB, and malaria, require the induction of cell-mediated immunity (CMI). Non-live vaccines have generally proven ineffective in producing CMI. In addition, although live vaccines may induce CMI, some live attenuated vaccines may cause disease in immunosuppressed subjects. As a result of these problems, several new approaches to vaccine development have emerged, such as recombinant protein subunits, synthetic peptides, protein polysaccharide conjugates, and plasmid DNA. While these new approaches may offer important safety advantages, a general problem is that vaccines alone are often poorly immunogenic. Therefore, there is a continuing need for the development of potent and safe adjuvants that can be used in vaccine formulations to enhance their immunogenicity. For a review of the state of the art in vaccine development see, e.g., Edelman, 2002, Molecular Biotech. 21: 129-148; O'Hagan et al., 2001, Biomolecular Engineering, 18: 69-85; Singh et al., 2002, Pharm. Res. 19(6):715-28)
Traditionally, the immunogenicity of a vaccine formulation has been improved by injecting it in a formulation that includes an adjuvant. Immunological adjuvants were initially described by Ramon (1924, Ann. Inst. Pasteur, 38: 1) “as substances used in combination with a specific antigen that produced a more robust immune response than the antigen alone”. A wide variety of substances, both biological and synthetic, have been used as adjuvants. However, despite extensive evaluation of a large number of candidates over many years, the only adjuvants currently approved by the U.S. Food and Drug administration are aluminum-based minerals (generically called Alum). Alum has a debatable safety record (see, e.g., Malakoff, Science, 2000, 288: 1323), and comparative studies show that it is a weak adjuvant for antibody induction to protein subunits and a poor adjuvant for CMI. Moreover, Alum adjuvants can induce IgE antibody response and have been associated with allergic reactions in some subjects (see, e.g., Gupta et al., 1998, Drug Deliv. Rev. 32: 155-72; Relyveld et al., 1998, Vaccine 16: 1016-23). Many experimental adjuvants have advanced to clinical trials since the development of Alum, and some have demonstrated high potency but have proven too toxic for therapeutic use in humans. Further, while a particular adjuvant may prove to be safe and efficacious in one tissue, the same agent may perform poorly or be toxic in another tissue space. Accordingly, each agent must be reevaluated as new delivery devices allow clinicians to reach new tissue spaces.
The existing vaccine formulations are usually administered several times over a time span of months in order to elicit an immune response that can confer protection on the host upon subsequent encounter with the antigen, e.g., microbe, itself. Thus, although vaccines for a variety of infectious diseases are currently available, many of these, including those for influenza, tetanus, and hepatitis B, require more than one administration to confer a protective benefit. These limitations are extremely problematic in countries where healthcare is not readily available or accessible. Moreover, compliance is also a problem in developed countries, particularly for childhood immunization programs.
Therefore, there is clearly an unmet need for more effective vaccine formulations and more effective means of delivering them to result in an enhanced therapeutic efficacy and protective immune response. Specifically, there is a need to develop vaccine formulations that reduce or eliminate the need for prolonged injection regimens.
2.2 Influenza Vaccines
The influenza viruses are divided into types A, B and C based on antigenic differences. Influenza A viruses are described by a nomenclature which includes the sub-type or type, geographic origin, strain number, and year of isolation, for example, A/Beijing/353/89. There are at least 15 sub-types of HA (H1-H13) and nine sub-types of NA (N1-N9). All sub-types are found in birds, but only H1-H3 and N1-N2 are found in humans, swine and horses (Murphy and Webster, “Orthomyxoviruses”, in Virology, ed. Fields, B. N., Knipe, D. M., Chanock, R. M., p. 1091-1152, Raven Press, New York, 1990). Influenza A and B virus epidemics can cause a significant mortality rate in older people and in patients with chronic illnesses.
Epidemic influenza occurs annually and is a cause of significant morbidity and mortality worldwide. Children have the highest attack rate and are largely responsible for transmission of influenza virus in the human community. The elderly and persons with underlying health problems, e.g., immuno-compromised individuals, are at an increased risk for complications and hospitalization from influenza infection. In the United States alone, more than 10,000 deaths occurred during each of the seven influenza seasons between 1956 and 1988 due to pneumonia and influenza, and greater than 40,000 deaths were reported for each of the two seasons (Update: Influenza Activity—United States and Worldwide, and Composition of the 1992-1993 Influenza Vaccine, Morbidity and Mortality Weekly Report. U.S. Department of Health and Human Services, Public Health Service, 41 No. 18:315-323, 1992). Typical influenza epidemics cause increases in incidence of pneumonia and lower respiratory disease, as witnessed by increased rates of hospitalization or mortality. The elderly or those with underlying chronic diseases are most likely to experience such complications, but young infants also may suffer severe disease. These groups, in particular, need to be protected.
Currently available influenza vaccines are either inactivated or live attenuated influenza vaccines. Inactivated flu vaccines comprise one of three types of antigen preparation: inactivated whole virus, sub-virions where purified virus particles are disrupted with detergents or other reagents to solubilise the lipid envelope (so-called “split” vaccine) or purified HA and NA (subunit vaccine). These inactivated vaccines are generally given intramuscularly (i.m.).
Influenza vaccines are usually trivalent vaccines. They generally contain antigens derived from two influenza A virus strains and one influenza B strain. A standard 0.5 mL injectable dose in most cases contains 15 μg of haemagglutinin antigen from each strain, as measured by single radial immunodiffusion (SRD) (Wood et al., 1977, J. Biol. Stand. 5: 237-247; Wood et al., 1981, J. Biol. Stand. 9: 317-330).
Current efforts to control the morbidity and mortality associated with yearly epidemics of influenza are based on the use of intramuscularly administered inactivated split or subunit influenza vaccines. The efficacy of such vaccines in preventing respiratory disease and influenza complications ranges from 75% in healthy adults to less than 50% in the elderly.
Therefore, there is clearly a need for an alternative way of administering influenza vaccines, in particular, a way that is pain-free or less painful than intramuscular injection, does not have the same risk of injection site infection, and does not involve the associated negative effect on patient compliance because of “needle fear”. Furthermore, it would be desirable to administer an influenza vaccine via an administration route that does not have negative effects on the health care worker, such as high risk of needle stick injury. Additionally, there is still an unmet need for a more therapeutically effective influenza vaccine formulation that reduces or eliminates the need for a prolonged injection regimen. and additionally reduces any type of irritation, beit local or systemic.